Note that the treatment involved an almond-size device placed behind the maxilla with a short lead projecting into the SPG, a nerve bundle that controls autonomic, sensory, and motor neural functions in the cranium.

Additionally, in the sham-controlled trial involving 43 patients, some two-thirds showed some type of response to the patient-controlled therapy, including reductions in attack severity, frequency, or both, according to Rigmor Jensen, MD, PhD, of Glostrup Hospital in Glostrup, Denmark, speaking at the International Headache Congress.

The treatment involved an almond-size device placed behind the maxilla with a short lead projecting into the sphenopalatine ganglion (SPG), a nerve bundle that controls autonomic, sensory, and motor neural functions in the cranium. Patients can turn the stimulation on by holding a cellphone-sized controller to their cheek. Removing the controller turns the stimulation off. The specific stimulation parameters, including frequency and voltage, are programmed into the controller by the physician or a technician.

About Cluster Headache

Distinct from migraines, cluster headaches are marked by unilateral pain felt around and behind the eye with a severity that can be extremely disabling. It is often accompanied by neurological effects including tearing and nasal discharge. The attacks are relatively infrequent in most patients -- occurring a few times annually -- but about 15% experience them daily. Patients in the current study reported attack frequencies ranging from four to 70 per week.

Jensen noted that the SPG has been considered the locus for cluster headache since 1908, and a number of treatments have been attempted. These included injections of various drugs and surgical procedures, with many of these showing good short-term results. But these approaches are still invasive and have to be repeated with each attack, while those aiming for a permanent solution have often had irreversible adverse effects.

Animal and early clinical studies had suggested that high-frequency electrostimulation delivered to the SPG would be both effective and reversible, Jensen said. A U.S.-based company called Autonomic Technologies developed the device used in the current study and provided the funding.

Further confirmation of the SPG's role in cluster headache was provided in another study reported here. Henrik Schytz, PhD, MD, reported results of a clinical study using the same Autonomic Technologies device showing that, with different settings than those used in the therapeutic trial, electrical stimulation can also induce cluster headaches.

Instead of the 80-120 Hz frequency used in the other study, Schytz's group set the device to rates of 5-60 Hz. In six patients who had received the device for therapeutic purposes, using this low-frequency setting produced immediate severe headache in three of them. Reverting to the normal high-frequency setting stopped the pain, Schytz said.

Short-Term Therapeutic Outcomes

The therapeutic results reported by Jensen and colleagues were not unexpected, as short-term outcomes in the first 32 patients treated in their study were published earlier this year in the journal Cephalalgia. But Jensen's oral presentation, as well as two related posters presented here included results from the entire cohort and extended to 1 year after implantation.

In the study, called CH-1, 43 patients were recruited, although five did not complete the initial treatment period. One became pregnant and was excluded, three had the device removed prematurely because of lead migration or improper positioning, and implantation failed in one. Jensen and colleagues reported data on the 38 who completed 3 to 8 weeks of active stimulator use, and on 28 who completed 1 year of follow-up.

The controller was set to randomly deliver full stimulation, imperceptible stimulation, or no stimulation at all for any given attack. Although patients were not told about the settings, they were not fully blinded because full stimulation is normally perceptible to patients.

Mean duration of illness was 10 years. At baseline, mean attack frequency was 16.8 per week and the mean HIT-6 headache disability score was 66.2 (SD 6.2), indicating severe disability. About two-thirds were taking verapamil for prophylaxis. For acute attacks, half of patients reported using oxygen therapy and all used triptans. Patients were allowed to use these acute treatments in addition to the stimulation at their discretion.

In 27% of attacks treated with the full stimulation, patients reported being completely pain-free within 15 minutes, Jensen said. In another 28%, patients said their pain was reduced to levels they considered mild.

For attacks in which the stimulators were not activated or in which the stimulation was at levels too low for patients to feel, only 6% to 7% reported complete or partial pain relief, Jensen's group stated.

Evaluations 90 minutes after patient-recorded attack onset indicated that complete pain relief had occurred in about 38% of attacks treated with full stimulation. Overall, 50% of treated attacks resulted in complete or partial relief within 90 minutes, compared with 13% of attacks treated with sham or imperceptible stimulation (P-value not reported).

The mean attack frequency declined to 11.1 per week at the end of the treatment period. Among 16 patients classed as frequency responders, showing at least a 50% decline in frequency, the mean decline was 89%, resulting a mean frequency of 1 per week.

Jensen and colleagues reported that 21% of patients were considered acute-phase responders for severity, for whom at least half of attacks resulted in complete or partial pain relief within 15 minutes. Another 42% showed at least a 50% reduction in attack frequency, and 8% were responders in both categories.

One-Year Follow-Up

After the initial treatment period of 3 to 8 weeks, patients then could choose to receive full stimulation on an open-label basis until 1 year after initial device implantation, at which point they were asked to complete a questionnaire about their overall experience.

Among the 28 patients completing the questionnaire, satisfaction was common, with 71% rating the overall system as good or very good, 71% calling it useful in treating their headaches, and 96% saying they would recommend it to other patients.

More than 90% indicated that the stimulation sensation was tolerable, 86% said the implanted component was comfortable or imperceptible when not activated, and 82% found the implantation procedure tolerable.

Most notably, Jensen said, about 11% of patients stopped using medications for their headaches and 29% reduced them. Only 14% said they had increased their use of prophylactic or rescue medications.

Peter Goadsby, MD, PhD, of the University of California San Francisco, and president of the International Headache Society, told MedPage Today that the technology appeared to be a promising option for patients with frequent cluster headaches not controlled with conventional therapies.

Goadsby had led much of the basic research confirming that the SPG was a viable target for electrostimulation in cluster headache, and has consulted for Autonomic Technologies but did not participate in the current clinical study.

He said that SPG stimulation would probably not replace verapamil or other standard medical therapies as first-line treatment for cluster headache, and wouldn't be appropriate at all for the majority of patients whose headaches occur only once or twice a year.

Rather, Goadsby said, it would likely rival occipital nerve stimulation as a second-line therapy and would push deep brain stimulation, currently a last-resort treatment, further back in the algorithm.

But he also noted that the studies to date with the SPG stimulator have been too small and too short to establish long-term safety and tolerability.

Additional Studies

Autonomic Technologies' device is currently approved in the European Union but not in the U.S. The firm is now conducting another randomized, controlled trial in Europe called M-1 with a projected 30 patients, and has promised to conduct one in the U.S. to support an FDA marketing application.

Also underway is a three-patient trial to determine if SPG stimulation can treat migraines. It was conceived by Stewart Tepper, MD, of the Cleveland Clinic, with support from Autonomic Technologies. But instead of using the firm's own stimulator, it is testing a different pulse generator manufactured by Medtronic for spinal cord stimulation, implanted in the shoulder with leads placed in the SPG.

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